Concomitant chemo/radiotherapy has improved the cure rates in many malignant neoplasms. This approach is limited by both systemic toxicity and adapted resistance. One solution is selective targeting at tumors with complimentary mechanisms, such as spatially and temporally controlled radiation, tumor-specific drug delivery, and blockades for tumor survival pathways. Our long term goal is to elucidate mechanisms of tumor response to radiation, and explore the mechanisms to improve therapeutic efficacy and decrease systemic toxicity of cancer radiotherapy. We isolated one short peptide that specifically binds to radiation-treated tumor microvasculature, the peptide sensitized tumor response to radiation in vitro and in vivo. We found that Tax- interacting protein 1 (TIP-1) is responsible for the peptide's specific binding within the irradiated tumor, radiation induces de novo synthesis and translocation of TIP-1 to cell membrane. This application is to study the biological roles of TIP-1 in tumor response to radiation, and utilize the tumor-selective peptide for tumor- targeted drug delivery. The significance of the proposed research is in studying a novel phenomenon of radiation-inducible expression and translocation of TIP-1 within tumor. Utilizing a peptide that selectively binds and sensitizes tumor to radiotherapy for tumor-targeted drug delivery will not only enhance efficacy of cancer radiotherapy by combining modalities of complementary mechanisms (radiation, inhibitory antibody or peptide, and delivered drug), but also reduce systemic toxicity by limiting cytocixity only within tumors since expression of the novel protein is strictly regulated by spatially and temporally controlled radiation. PUBLIC HEALTH RELEVANCE: We discovered radiation induces de novo synthesis and membrane translocation of TIP-1, which may mediate cytotoxic effect of one tumor-selective peptide on irradiated tumors. This application is to study biological roles of TIP-1 in tumor response to radiation, and utilize the tumor-selective peptide for tumor- targeted drug delivery.